Project Summary The majority of Americans will experience a traumatic event during their lifetimes, but women are twice as likely as men to experience negative psychiatric outcomes following trauma such as post-traumatic stress disorder (PTSD) and depression. The reason for the increased prevalence in women is unclear, partially because of the historical lack of investigation of females in both human and pre-clinical animal research. In the proposed research, we will investigate the role of sex hormones in contributing to women's risk for PTSD. The gonadal hormone estradiol (E2) has previously been associated with emotion regulation and fear extinction in rodent and healthy human studies, mediated by plasticity in pathways between the amygdala and regulatory inputs from the prefrontal cortex and hippocampus. Women with PTSD show clear deficits in regulating emotional arousal, and in fear extinction learning. We will test the hypothesis that low E2 contributes to these deficits by experimentally manipulating E2, and studying its effects on fMRI measures of threat reactivity and fear extinction, in women with PTSD, trauma-exposed women without PTSD, and healthy controls. We will use a randomized double-blind, placebo-controlled, within-subjects crossover design, with E2/placebo given to naturally-cycling women during the early follicular phase of the cycle when endogenous E2 is lowest. Participants will be randomized to E2 or placebo at the first MRI scan, and will cross over to the other condition for a second scan conducted at the same point in the subsequent menstrual cycle. Secondly, given existing observational evidence that PTSD risk/symptoms are heightened during the luteal phase, we will test this E2 administration in the luteal phase to observe whether an increase in the E2-progesterone ratio reduces PTSD symptoms and impairments in threat reactivity and fear extinction in this time of heightened risk. The research environment at Emory University School of Medicine will provide excellent support for the successful completion of the proposed research, particularly with state of the art neuroimaging facilities, a well-developed infrastructure for identifying participants at risk for trauma and PTSD through the Grady Trauma Project, and a strong community of experts in trauma, neuroendocrine, neuroimaging, and women's health research. Findings from this study may aid in the development of new treatments and interventions to increase women's mental health outcomes following trauma.